Persistent reversal of tolerance to anticonvulsant effects and GABAergic subsensitivity by a single exposure to benzodiazepine antagonist during chronic benzodiazepine administration.

The persistence of benzodiazepine antagonists in reversing neuronal and behavioral tolerance during chronic diazepam exposure was examined in rodents by investigating the time course for antagonist-induced alterations in iontophoretic sensitivity to gamma-aminobutyric acid on dorsal raphe neurons and the re-emergence of anticonvulsant efficacy to bicuculline-induced seizures. In these studies, exposure to Ro15-1788 resulted in the persistent reversal of GABAergic subsensitivity and restoration of anticonvulsant actions of diazepam despite the continued presence of diazepam in the rats. Reversal of tolerance appears to persist for up to 7 days after a single exposure to benzodiazepine antagonists.